Ebselen Is a Dehydroascorbate Reductase Mimic, Facilitating the Recycling of Ascorbate via Mammalian Thioredoxin Systems

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Abstract
Ebselen is a selanazal drug recently revealed as a highly efficient peroxiredoxin mimic catalyzing the hydroperoxide reduction by the mammalian thioredoxin system [thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH]. The mammalian Trx system is a dehydroascorbic acid reductase recycling ascorbic acid essential for cell functions. Here we report that ebselen strongly facilitated the recycling of ascorbic acid by the TrxR both with and without Trx present. Reduction of dehydroascorbic acid by TrxR has a pH optimum of 6.4, and only approximately 55% of this activity at a physiological pH of 7.4. Ebselen at 6 microM enhances this reaction three-fold and with the same pH optimum of 6.4. The mechanism of the ebselen effect is suggested to involve reduction of dehydroascorbic acid by the ebselen selenol, a highly efficient two-electron reductant. Thus, ebselen acts as an antioxidant to lower the peroxide tone inside cells and to facilitate the recycling of dehydroascorbic acid to ascorbic acid, so as to increase the radical scavenging capacity of ascorbic acid directly or indirectly via vitamin E. The high ascorbic acid recycling efficiency of ebselen at pH 6.4 may play a major role in oxidatively stressed cells, where cytosol acidosis may trigger various responses, including apoptosis.